The immediate objective of this application is to provide high level pre-doctoral research training to Mr. Daniel Miller. Head and neck squamous cell carcinoma (HNSCC) is the 6th most commonly diagnosed cancer worldwide, with a half-million annual diagnoses, >200,000 deaths annually, and US deaths occurring at a rate of 1 death/hour. Molecular studies have revealed that 40-80% of oropharyngeal squamous cell carcinomas (OPSCC) diagnosed in the US contain human papilloma virus (HPV). The incidence of OPSCC has increased significantly at a rate of 1.3% and 0.6% yearly between 1973 and 2004 for base of tongue and tonsillar carcinomas, respectively. Although epidemiological and molecular studies support HPV+ OPSCC as a distinct clinical entity, the pathobiology of HPV-associated OPSCC initiation and progression is poorly understood. A more detailed understanding of molecular events associated with HPV+ OPSCC progression is therefore a prerequisite for improved staging and diagnostic/prognostic stratification. MicroRNAs (miRNA) are small non-coding RNAs that participate in post-transcriptional gene silencing by regulating mRNA translation, thereby significantly altering the protein output of a cell. Unlike many DNA viruses that express their own miRNAs, papillomaviruses instead alter the expression of cellular miRNAs; however the relationship between HPV status and miRNA profiles in OPSCC has not been evaluated. To address this significant gap, the current proposal will test the hypothesis that HPV+ OPSCC lesions display distinct miRNA profiles and that alterations in specific miRNAs contribute to disease progression. To investigate this hypothesis, we will conduct microRNA profiling of HPV+ and HPV- OPSCC tumors, perform functional analysis of miRNA-modified cells, and generate transcriptomic and proteomic profiles of miRNA-modified OPSCC. The completed project will provide important insight into the disease entities of HPV+ and HPV- OPSCC with potential to improve diagnostic and therapeutic strategies.